Early-life exposure to harmless microbes, as occurs through exposure to children, pets, and farm animals, is increasingly understood to affect childhood health, and mounting evidence suggests that these exposures also influence health in adulthood. The likely pathway for this influence involves a calibrating effect of early-life microbial exposures on the immune response so as to reduce the likelihood of chronic inflammation in later life. As chronic inflammation is known to interact with hormone levels and is suspected in the cause of several cancers in women, including breast, endometrial, and colon cancers, microbial exposures represent important targets of cancer prevention studies. We have preliminary evidence that early-life exposure to farming and preschool or kindergarten protects against breast cancer risk later in life, justifying more detailed study of these exposures for breast and other cancers, including how the risk associations might vary with age-specific exposures across the lifespan. We have a unique opportunity to examine relationships between microbial exposures and cancer risk in over 60,000 women participating in the California Teachers Study (CTS), a cohort of female California teachers and administrators followed prospectively for cancer incidence since 1995. Our study aims to measure associations between selected markers of microbial burden at a range of ages and risk of several cancer outcomes, including in situ breast cancer, estrogen receptor (ER)-positive and ER-negative invasive breast cancer, type 1 endometrial cancer, cutaneous melanoma, colon cancer, and, to the extent possible, papillary thyroid cancer. To accomplish these aims, we will conduct a secondary data analysis in the CTS, using a nested case-control design, using exposure data collected from 60,878 cohort members who provided information about five markers for microbial exposure, including characteristics of their home environment at ages 6 months, 3 years, 5 years, 12 years, and 30 years. We will use unconditional logistic regression to measure associations adjusted for confounders such as age and socioeconomic status. This unified approach will enable us to compare and contrast in a single cohort the associations of early- and later- life markers of microbial exposures with risk of hormone-dependent cancers (e.g., ER-positive breast, endometrial, and papillary thyroid cancers), hormone-independent cancers (e.g., melanoma and ER-negative breast cancer), and cancers linked strongly to chronic inflammation (e.g., breast and colon cancers). If we find that these understudied environmental exposures do reduce risk of specific cancers or groups of cancers, our results could justify the investigation of new cancer prevention strategies using harmless surrogates of important microbial exposures. PUBLIC HEALTH RELEVANCE: Exposure in early life to harmless microbes, as occurs through contact with children, pets, and farming environments, could prevent certain cancers in later life through a calibrating effect on the immune system. This study, based in a large cohort of California women, will examine whether age-specific markers of microbial exposures are associated with the risk of developing malignancies that together account for a large proportion of the cancer burden in US women, including cancers of the breast, endometrium, colon, thyroid, and melanocyte. If this study finds that these microbial exposures do reduce cancer risk, our results could justify the investigation of new cancer prevention strategies using harmless surrogates of important microbial exposures.